Single Cell Genomics to Resolve Control of Immune Cell Function During Type 1 Diabetes

单细胞基因组学解决 1 型糖尿病期间免疫细胞功能的控制问题

基本信息

批准号：
10728072
负责人：
Rachel S Friedman
金额：
$ 21.97万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-26 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10728072
关键词：
ATAC-seq Address Antigens Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity B-Lymphocytes Bar Codes Beta Cell Biological Assay CD8-Positive T-Lymphocytes Cell physiology Cells Chronic Chronic Disease Clinical DNA Data Disease Disease Progression Exposure to Family Gene Expression Profile Genes Genetic Transcription Genomic approach Genomics Goals Human Immune Immune response Inbred NOD Mice Individual Infection Infiltration Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Leucine Zippers Link Macrophage Malignant Neoplasms Methods Molecular Mus Myelogenous Myeloid Cells Outcome Pancreas Pathogenesis Pattern Population Protocols documentation Publishing Regulation Resolution Structure of beta Cell of islet T cell infiltration T cell regulation T cell response T-Lymphocyte Techniques Testing Transcriptional Regulation Virus Work advanced disease autoreactive T cell autoreactivity cell type cytokine disorder control exhaust exhaustion experimental study functional genomics immune cell infiltrate immune function insulin dependent diabetes mellitus onset islet mouse model novel programs receptor response single-cell RNA sequencing therapeutic target transcription factor tumor

项目摘要

PROJECT SUMMARY T cells specific for pancreatic beta cell antigens drive an autoimmune response leading to type 1 diabetes (T1D). During the onset of T1D, many immune cell types infiltrate into pancreatic islets, but the infiltration of each individual islet varies substantially within an individual mouse or human. Additionally, the interactions between immune cells and resident islet cells vary over the immune response within the microenvironment of an individual islet from infiltration and initial activation to a period of regulation before eventual destruction. A better understanding of factors that control autoreactive T cell function in the islets could lead to therapies for T1D that target the underlying mechanisms that cause disease. Based on our published work and new preliminary data, our central hypothesis is that autoreactive CD8+ T cell destruction of beta cells is determined by activation of the basic region leucine zipper (bZIP) transcription factors in response to the islet antigens and the local cellular microenvironment. We predict that these programs are differentially induced in CD8+ T cells by the cellular microenvironment of each individual islet. We propose two aims to test these predictions during onset of T1D in NOD mice using novel single cell functional genomics approaches. In Aim 1 we will determine the contribution of the bZIP transcription factors family to autoreactive T cell function in the pancreas. In Aim 2 we will determine impact of macrophages on the transcriptional programs of individual cells between separate pancreatic islet microenvironments. The expected results of our study will address unanswered questions about the fundamental mechanisms controlling T cell activity and immune cell interplay during autoimmune disease.

项目概要胰腺 β 细胞抗原特异性 T 细胞驱动自身免疫反应，导致 1 型糖尿病（T1D）。在 T1D 发病期间，许多免疫细胞类型浸润到胰岛，但每种类型的浸润个体小鼠或人体内的个体胰岛差异很大。此外，之间的相互作用免疫细胞和常驻胰岛细胞在个体微环境内的免疫反应上有所不同胰岛从渗透和初始激活到最终破坏之前的一段调节期。更好的了解控制胰岛自身反应性 T 细胞功能的因素可能会导致 T1D 的治疗方法针对导致疾病的潜在机制。根据我们发表的工作和新的初步数据，我们的中心假设是，β 细胞的自身反应性 CD8+ T 细胞破坏是通过激活碱性区亮氨酸拉链 (bZIP) 转录因子响应胰岛抗原和局部细胞微环境。我们预测这些程序在 CD8+ T 细胞中由细胞每个胰岛的微环境。我们提出了两个目标来测试 T1D 发病期间的这些预测 NOD 小鼠使用新型单细胞功能基因组学方法。在目标 1 中，我们将确定贡献 bZIP 转录因子家族与胰腺中自身反应性 T 细胞功能的关系。在目标 2 中，我们将确定巨噬细胞对不同胰岛之间单个细胞转录程序的影响微环境。我们研究的预期结果将解决有关基本原理的未解答问题自身免疫性疾病期间控制 T 细胞活性和免疫细胞相互作用的机制。